Building a macrocyclic toolbox from C-linked carbohydrates identifies antiangiogenesis agents from zebrafish assay

Article abstract of DOI:10.1002/ejoc.201300548

We report the synthesis of four different types of macrocyclic-derived glycohybrids from carbohydrates that have an amino acid moiety in the large-ring skeleton. These macrocyclic glycohybrids were obtained from α-C-1H- and β-C-1H-linked carbohydrates. In one series, we utilized ring-closing metathesis as the "stitching technology" to obtain two different macrocycles, i.e., trans equatorial-axial C-1H and C-5H and cis axial-axial C-1H and C-5H. The click approach was the key reaction in our second series to obtain two other macrocyclic compounds, i.e., trans equatorial-axial C-1H and C-5H and cis axial-axial C-1H and C-5H. The evaluation of this toolbox resulted in the identification of two unique compounds as antiangiogenesis agents in an embryonic zebrafish assay. Interestingly, in both cases, the macrocyclic compounds that have a cis relationship (i.e., axial-axial orientation) between C-1H and C-5H showed activity and their other diastereomers (i.e., equatorial-axial C-1H and C-5 H) with a trans relationship did not show any effect. The synthesis of four different types of macrocyclic glycohybrids that contain an amino acid moiety in the large-ring skeleton is reported. Ring-closing metathesis and click chemistry approaches were utilized to obtain two different series of macrocycles. The evaluation of this toolbox resulted in the identification of two unique compounds as antiangiogenesis agents in an embryonic zebrafish assay. Copyright

Full text of DOI:10.1002/ejoc.201300548

Job/Unit: O30548
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SHORT COMMUNICATION
Antiangiogenesis Agents
S. Jogula, B. Dasari, M. Khatravath,
G. Chandrasekar, S. S. Kitambi,*
P. Arya* ............................................ 1–6
Building a Macrocyclic Toolbox from C-
Linked Carbohydrates Identifies Anti-
angiogenesis Agents from Zebrafish Assay
The synthesis of four different types of
macrocyclic glycohybrids that contain an
amino acid moiety in the large-ring skel-
eton is reported. Ring-closing metathesis
and click chemistry approaches were util-
ized to obtain two different series of macro-
cycles. The evaluation of this toolbox re-
sulted in the identification of two unique
compounds as antiangiogenesis agents in
an embryonic zebrafish assay.
Keywords: Macrocycles / Medicinal chemis-
try / Carbohydrates / Click chemistry / An-
giogenesis / Molecular diversity
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Date: 03-07-13 10:12:15
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S. S. Kitambi, P. Arya et al.
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300548
Building a Macrocyclic Toolbox from C-Linked Carbohydrates Identifies
Antiangiogenesis Agents from Zebrafish Assay
Srinivas Jogula,[a] Bhanudas Dasari,[a] Mahender Khatravath,[a] Gayathri Chandrasekar,[b]
Satish Srinivas Kitambi,*[b,c,d] and Prabhat Arya*[a]
Keywords: Macrocycles / Medicinal chemistry / Carbohydrates / Click chemistry / Angiogenesis / Molecular diversity
We report the synthesis of four different types of macrocyclic-
derived glycohybrids from carbohydrates that have an amino
acid moiety in the large-ring skeleton. These macrocyclic
glycohybrids were obtained from α-C-1H- and β-C-1H-
linked carbohydrates. In one series, we utilized ring-closing
metathesis as the “stitching technology” to obtain two dif-
ferent macrocycles, i.e., trans equatorial–axial C-1H and C-
5H and cis axial–axial C-1H and C-5H. The click approach
was the key reaction in our second series to obtain two other
macrocyclic compounds, i.e., trans equatorial–axial C-1H
and C-5H and cis axial–axial C-1H and C-5H. The evaluation
of this toolbox resulted in the identification of two unique
compounds as antiangiogenesis agents in an embryonic ze-
brafish assay. Interestingly, in both cases, the macrocyclic
compounds that have a cis relationship (i.e., axial–axial ori-
entation) between C-1H and C-5H showed activity and their
other diastereomers (i.e., equatorial–axial C-1H and C-5 H)
with a trans relationship did not show any effect.
combined together offer several advantages on the use of
various types of macrocyclic compounds. A particular at-
traction in having macrocycles from sugars is that one can
nicely synthesize amphiphilic macrocyclic skeletons to ex-
plore their biological function(s).
Introduction
In continuation of our interest in building a glyco-based
macrocyclic toolbox to search for modulators of protein–
protein,[1,2] DNA/RNA–protein[3] interactions and the dis-
sectors of signalling pathways,[4] herein, we outline another
strategy to obtain a different family of glycohybrids.[5–10] As
briefly discussed in our recent papers,[11,12] the need to ac-
cess compounds that bear a closer resemblance to natural
products in terms of their 3D architecture and the presence
of several chiral functional groups is growing con-
stantly.[13–15] There is a particular rise in the interest in func-
tionalized macrocyclic compounds,[16] which can provide
several advantages, such as (1) being useful to map a large
surface area to explore macromolecular interaction-based
targets, (2) a functionalized macrocycle can provide numer-
ous binding interaction possibilities, (3) amphiphilic macro-
cyclic compounds can be useful to maintain a balance
through various polar/non-polar sites. All these features
Results and Discussion
In our earlier approach,[11a] we reported a modular syn-
thesis of 14-membered macrocyclic compounds as gly-
cohybrids that were derived from a pyran ring opening, fol-
lowed by incorporation of the amino acid moiety, and fi-
nally, through application of the stitching technology.[17]
Herein, we propose a route to obtain C-linked β- and α-
glycosyl carboxyl esters 1.2 and 1.3 (Scheme 1) that are
known in the literature.[18a] The presence of two functional
groups on the sugar moiety, i.e., the carboxyl ester side
chain at C-1 and the primary hydroxy group at C-5 means
that compounds 1.2 and 1.3 can easily be coupled to vari-
ous amino alcohols, which can then be subjected to the
ring-closing technology to give the 15-membered macro-
cyclic rings 1.4 and 1.5.[18b] The proposed plan is general in
nature and can be applied to several sugars to allow varia-
tion in the three hydroxy groups at C-2/3/4 that are incorpo-
rated in the macrocyclic ring. Due to the general nature of
this method, one can utilize different sugars to obtain diver-
sity in the contiguous hydroxy groups that are present in
the 15-membered macrocyclic ring. Shown in Scheme 2 are
two different macrocyclic glycohybrids 2.2 and 2.3 that we
planned to obtain from methyl α-d-glucopyranoside 2.1.
[a] Dr. Reddy’s Institute of Life Sciences, University of Hyderabad
Campus,
Gachibowli, Hyderabad 500046, India
E-mail: prabhata@drils.org
Homepage: www.prabhatarya.org
[b] School of Life Sciences, Södertörns Högskola,
14189 Huddinge, Sweden
[c] Department of Biosciences and Medical Nutrition,
Karolinska Institutet, 17177 Stockholm, Sweden
[d] Division of Molecular Neurobiology, Department of Medical
Biochemistry and Biophysics, Karolinska Institutet,
Karolinska Institutet, 17177 Stockholm, Sweden
E-mail: satish.kitambi@ki.se
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300548
2
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Building a Macrocyclic Toolbox from C-Linked Carbohydrates
Scheme 3. 14-Membered macrocycles by click stitching technology.
Scheme 1. Our approach to utilize C-linked glyco-derivatives 1.2
and 1.3 to access macrocyclic glycohybrids 1.4 and 1.5.
genation to obtain 5.2ah and 5.2bh for NOE studies. This
In another approach, we planned to obtain glyco-based helped in assigning the diagnostic C-1H (i.e., C-1-α-H
sugar azido esters 3.1 and 3.2 (Scheme 3) from 1.1 and the 3.66 ppm and C-1-β-H 4.44 ppm) in both cases. The de-
synthesis of these two compounds has been reported in the tailed analytical information is provided in the Supporting
literature.[19] In our approach, we planned to incorporate Information. On a large scale, the mixture as a whole was
the amino acid moiety through coupling with the carboxyl subjected to selective debenzylation conditions that gave the
functional group of sugar azido acids and then utilize the free hydroxy group at C-5, which upon allylation and ester
click-chemistry-based stitching technology.[20–24]
hydrolysis gave the free carboxylic acid as 5.3. It was then
This strategy to obtain glycohybrids containing 14-mem- coupled to several O-allylated chiral amines 5.4, which were
bered rings has some unique features and they are worth easily obtained from their corresponding amino acids in
mentioning. These include the building of 14-membered four steps (for the detailed synthesis steps, see the Support-
macrocyclic ring that has a bridged sugar utilizing either ing Information). This led to the formation of the coupled
the trans C-1H and C-5H or cis C-1H and C-5H (see, 3.3 products as a separable, 1:1 diastereoemeric mixture at C-1
and 3.4). In addition to this, they also have another bridged as 5.5 and 5.6. Both of these compounds were then thor-
heterocyclic ring arising from the click reaction. The varia- oughly purified as pure products and well characterized by
tion in C-1 stereochemistry leads to two different macro- NMR spectroscopy and MS (note: the stereochemistry at
cyclic compounds to allow the display of various functional C-1H in both cases was assigned after the macrocycliza-
groups in different orientations. Once again, this method is tion).
versatile and several sugars can be utilized to obtain the
contiguous hydroxy group presentation on the sugar ring.
This set the stage to test our crucial ring-closing meta-
thesis reaction on these two highly functionalized starting
A specific example of two macrocyclic compounds, 4.1 materials. We were pleased to observe that in both cases the
and 4.2, is shown in Scheme 4. Our detailed synthesis plan stitching technology carried out with Grubbs 2nd generation
to obtain 15-membered rings is shown in Scheme 5. To start 5 mol-% catalyst gave the desired products 5.7 and 5.8. In
with, methyl α-d-glucopyranoside was converted to 5.2, a both cases, the product with the trans olefin geometry was
C-linked carboxyl ester derivative, as an unseparable dia- obtained. Once again, based on the diagnostic C-1H value
stereomeric mixture. As a test study, the diastereomeric in the proton NMR spectra (i.e. C-1-α-H 3.50 ppm and C-
mixture of 5.2 was separated in a small amount as 5.2a 1-β-H 4.62 ppm), the corresponding products were assigned
(lower Rf, C-1-β-H, 4.68 ppm) and 5.2b (higher Rf, C-1-α- with the correct stereochemistry, i.e., C-1-α-H for 5.7 and
H 3.76), and both products were further subjected to hydro- C-1-β-H for 5.8. In both series, one example, as a test case,
Scheme 2. Macrocyclic glycohybrids, 2.2 and 2.3, from methyl-α-d-glucopyranoside 2.1.
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SHORT COMMUNICATION
Scheme 4. Macrocyclic glycohybrids 4.1 and 4.2 from methyl-α-d-glucopyranoside 2.1.
Scheme 5. Synthesis of glycohybrid macrocyclics 1.4 and 1.5 (a) (i) NaH, BnBr, DMF, room temp., 18 h, 94%; (ii) 2 n HCl, AcOH, 90–
95 °C, 6 h, 50%; (iii) NaH, triethyl phosphonoacetate, 0 °C to room temp., 16 h, 85%; (b) ZnCl2, Ac2O/AcOH (2:1), room temp., 2 h;
(ii) K2CO3, MeOH, room temp., 16 h, 80% for 2 steps; (iii) NaOH, allyl bromide, THF, 0 °C to room temp., 16 h, 90%; (c) 5.4a–d,
EDCI·HCl, MeCN, room temp., 1 h, 90–95%; (d) 5 mol-% Grubbs 2nd gen. cat., CH2Cl2, reflux, 16 h, 55–65%; (e) 10% Pd/C, H2, EtOH,
24 h, 70–75%.
was subjected to hydrogenation conditions that gave the de- seprable 1:1 diasteroemric mixture of 6.3. This was then
sired products 2.2 and 2.3 with the free hydroxy groups on subjected to a click reaction that worked well as a suitable
the sugar part of the bridged macrocycles. It is worth men- stitching technology to obtain two separable diastereomeric
tioning here that all the intermediates at different steps in products 6.4 and 6.5. Both of them were thoroughly puri-
our synthesis are stable at room temperature and are easy fied and well characterized by NMR spectroscopy and MS.
to handle.
In the case of 6.4c, the NOE studies confirmed the cis 1,3-
Our second approach to obtain 14-membered glycohyb- dixial orientation for C-1H and C-5H and the trans 1,3-
rids containing two bridged rings, one from the sugar pyran orientation for C-1H (equatorial) and C-5H (axial) for 6.5c.
moiety and the other is the five membered heterocyclic ring The detailed synthetic procedure is provided in the Sup-
from the click stitching technology is shown in Scheme 6. porting Inoformation. These fused macrocyclic compounds
The diastereomeric mixture of C-linked carboxyl ester 5.2 are unique and a nice blend of sugar pyran moiety along
was converted into the corresponding azido carboxylic acid with the 5-membered heterocyclic ring onto the 14-mem-
6.1 in five steps. The free carboxylic acid group was then berd macrocyclic skeleton. As before, in one test study, the
coupled with 6.2, a propargyl derivative that can be easily compounds were subjected to hydrogenation conditions to
obtained from various amino acids, to obtain, an un- remove the benzyl groups to obtain the free hydroxy groups
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Building a Macrocyclic Toolbox from C-Linked Carbohydrates
Scheme 6. Glyocohybrid-based macrocycles by a click approach (a) (i) ZnCl2, Ac2O/AcOH (2:1), room temp., 2 h; (ii) K2CO3, MeOH,
room temp., 16 h, 80% for 2 steps (iii) MsCl, TEA, CH2Cl2, room temp., 1 h; (iv) NaN3, DMF, 80 °C, 16 h, 90% for 2 steps; (v) 1 m
NaOH, THF, H2O, 4 h; (b) 6.2a–d, EDCI·HCl, MeCN, 2 h, 65–75% for 2 steps; (c) CuI, DIPEA, THF, 80 °C, 4 h, 55–65%; (d) 10%
Pd/C, H2, EtOH, 16 h, 80–85%.
on the sugar moiety. Once again, the cis C-1H and C-5H esis of more than 50% of vessels. The dose-response experi-
(axial–axial) and trans C-1H and C-5H (equatorial–axial) ments were performed with both hit compounds (5.7a and
offer unique ways of presenting various functional groups 5.7d) and sharp effects were observed between 2.5–5.0 μm
onto the 14-membered ring skeleton and it would be nice concentrations. It is interesting to note that both active
to see the difference in their biological function as a prop- compounds are similar in their structures and only differ in
erty of the stereodifferentiation of the stereogenic centre, the nature of the chiral side chain arising from the amino
i.e., C-1 in 6.4 and 6.5.
acid moiety. Both compounds have cis axial–axial C-1H
Zebrafish Screen for Antiagniogenesis Agents
All the compounds obtained from this project (33 in to-
tal) were then subjected to embroynic zebrafish screen for
antiangiogenesis. Zebrafish are an attractive, rapid and
cheap way to evaluate the scope of small molecules in vari-
ous assays that are close to an in vivo type environ-
ment.[25,26] Over the years, zebrafish have been well utilized
to search for compounds with antiangiogenesis proper-
ties.[27–35] The details of the experimental procedure are pro-
vided in the Supporting Information. Of all the compounds
tested for the angiogensis screen, we identified two novel
glycohybrid-based macrocyclic compounds (5.7a and 5.7d,
Figure 1) as inhibitors of angiogensis. For example, both
compounds exhibited a partial inhibition at 2.5 μm and
complete inhibition at 5.0 μm. The severe effect was seen
as the complete inhibition of angiogenesis and the partial
Figure 1. Embryonic zebrafish assay for angiogenesis: (a) zoom sec-
tion of wild-type or vehicle-treated embryo; (b) control; (c) and (d):
zoom sections after the treatment with macrocyclic compounds
5.7a and 5.7d (noteϪthe figures are shown only with the use of
inhibition was characterized by the inhibition of angiogen- compound 5.7a).
Figure 2. Acyclic precursors of 5.7a and 5.7d and two related macrocyclic compounds (i.e., having a diasteromeric carbon at C-1) did
not show any effect on angiogenesis in a zebrafish screen.
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SHORT COMMUNICATION
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Conclusions
To summarize, using sugar as the starting material, we
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Published Online: ᭿
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